Manifold amplification of in vivo immunity in normal and immunodeficient mice by ribonucleosides derivatized at C8 of guanine.

Antigen-specific lymphocyte activation is generally thought to be initiated by the binding of antigen to specific membrane receptors, followed by transduction of a signal across the cell membrane. In addition, at least two supplementary signals apparently are required for induction of specific antibody synthesis. Various exogenous agents have been shown to augment the magnitude of specific responses to antigen. Certain of these adjuvants are polyclonal activators as well. We recently described a new class of activator, the C8-substituted-guanine ribonucleosides, that traverses the cell membrane and bypasses classical triggering mechanisms to activate the lymphocyte at an intracellular site. The current studies demonstrate that this new class of activator exerts powerful in vivo adjuvant activity when administered to mice after antigen. This effect is highly dose- and time-dependent. When nucleoside administration is delayed until 3-4 days after immunization, enhancement of the response persists but the optimal dose of nucleoside decreases by 2 orders of magnitude, indicating that these compounds are highly effective modulators of the immune response well after the initiating events have occurred. Amplification of the antibody response occurs over a wide range of antigen concentrations but is maximal at optimal antigenic concentrations. Enhancement of antibody responses in vivo is absolutely dependent upon derivatization of guanosine at C8; native guanosine is ineffective. When administered after antigen (sheep erythrocytes) to male (CBA/N X CBA/CaJ)F1 mice (which bear the xid B-cell defect) in an effort to bolster their impaired response to this T cell-dependent antigen, the brominated nucleoside induced a degree of responsiveness equivalent to that generated in the normal (female) counterparts injected with antigen and 8-bromoguanosine.